Project Summary/Abstract Clinical trials of Alzheimer's disease (AD) therapeutics have had the highest failure rate of any major disease, with only 1 compound approved of 244 compounds tested during 2002-2012 (Cummings, 2014). The majority of these compounds target known pathological processes such as beta amyloid (?-amyloid) processing or neurotransmitter system imbalance, and the failure of these trials highlights the urgent need for new biological approaches to treat AD. One new approach is to target the epigenetic mechanisms that are integral to learning and memory encoding. Histone H3 lysine 9 (H3K9) is a key target for methylation, with di and trimethylation of this site serving as transcriptional repressors. In preliminary data, we have discovered that H3K9 trimethylation (H3K9me3) increases with age in the hippocampus and is associated with cognitive decline in aged and AD transgenic mice. Notably, selective inhibition of the methyltransferase controlling H3K9 trimethylation (SUV39H1) with a newly developed pharmacological small molecule inhibitor (ETP69) dramatically improves hippocampus-dependent memory in aged and transgenic AD mice (but not young mice), opens repressive chromatin structure at genes required for memory formation, increases hippocampal BDNF levels, promotes transcription of NR4a2, and stimulates growth of dendritic spines, thus restoring key mechanisms commonly proposed for synaptic dysfunction with age and AD. This suggests that an approach for treating AD may be to target a specific epigenetic mechanism (H3K9me3) involved in the coordinate regulation of gene expression required for normal brain function. In this proposal we will build on our preliminary data and test the hypothesis that H3K9me3 levels and distribution regulated by SUV39H1 become unbalanced in the aging brain and exacerbate AD-related phenotypes. Such an unbalance may form the basis for the etiological complexity of AD. We will test the possibility that H3K9me3 is a key nodal repression point for cognitive decline associated with aging and AD, and that reducing H3K9me3 restores lost cognition in wild type and AD transgenic mouse models. We propose three Specific Aims: (1) How does H3K9 trimethylation in the hippocampus shift over the lifespan, do H3K9me3 levels on target genes predict declining hippocampus-dependent cognition, and are benefits of SUV39H1 suppression predicated by elevated H3K9me3 levels? (2) Is H3K9me3 accumulation accelerated by AD pathology (?-amyloid, oxidative stress) and is SUV39H1 suppression effective even in the presence of high pathology? (3) Using ChIP-seq and RNA-seq, what are the SUV39H1/H3K9me3 molecular events that drive the effects on cognition? Overall our studies will define a new mechanism controlling cognitive decline in aging and AD and profile an exciting new pharmacological approach to rebalance gene repression patterns and restore cognitive function.